title: Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology.
abstract: The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR(-/-) mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR(-/-) mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.
authors.affiliation: Departments of Ophthalmology, Pathology, and Pharmacology and Cancer Biology, Duke University, Durham, NC 27710.
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.forename: Rolf
authors.initials: R
authors.lastname: Herrmann
authors.forename: Amanda
authors.initials: A
authors.lastname: Bednar
authors.forename: Peter
authors.initials: P
authors.lastname: Saloupis
authors.forename: Mary A
authors.initials: MA
authors.lastname: Dwyer
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Jaffe
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: Goldis
authors.initials: G
authors.lastname: Malek
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002460:Cell Line; D002648:Child; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008875:Middle Aged; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D008062:Lipofuscin; D008077:Lipoproteins, LDL; D018336:Receptors, Aryl Hydrocarbon
keywords: oxidized low density lipoprotein; retinal disease; retinal pigment epithelium; toxin metabolism